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Design of Small Molecules That Compete with Nucleotide Binding to an Engineered Oncogenic KRAS Allele
Open accessAbstract
RAS mutations are found in 30% of all human cancers, with KRAS the most frequently mutated among the three RAS isoforms (KRAS, NRAS, and HRAS). However, directly targeting oncogenic KRAS with small molecules in the nucleotide-binding site has been difficult because of the high affinity of KRAS for GDP and GTP. We designed an engineered allele of KRAS and a covalent inhibitor that competes for GTP and GDP. This ligand-receptor combination demonstrates that the high affinity of GTP and GDP for RAS proteins can be overcome with a covalent inhibitor and a suitably engineered binding site. The covalent inhibitor irreversibly modifies the protein at the engineered nucleotide-binding site and is able to compete with GDP and GTP. This provides a new tool for studying KRAS function and suggests strategies for targeting the nucleotide-binding site of oncogenic RAS proteins.
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Designing small molecules that block the GTP binding site on K-Ras is challenging because K-Ras has extremely high affinity for GTP.
“Second, the efforts of trying to design small molecules blocking the GTP binding site on K-Ras have been challenging, given the extremely high affinity of K-Ras for GTP.41,45”
From Overcoming Resistance to Drugs Targeting KRAS Mutation (2020) · cites this paper as [45]
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Metadata
- Authors
- Zhang, Y., Larraufie, M.-H., Musavi, L., Akkiraju, H., Brown, L. M., & Stockwell, B. R.
- Affiliations
- Columbia University (US)
- Corresponding author
- Stockwell, Brent R.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-02-06
- Volume
- 57
- Issue
- 8
- Pages
- 1380-1389
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC5960803
- OpenAlex
- W2784124279
- Cited by
- 16
- References
- 36
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 2 · 2020: 2 · 2019: 2 · 2018: 2
- FWCI
- 0.53
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (P01CA087497, R21CA177591, R35CA209896)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS, RAS mutations, nucleotide binding site, covalent inhibitors, small molecule inhibitors, protein modification
- MeSH terms
- Amino Acid Sequence, Binding Sites, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Models, Molecular, Mutation, Protein Binding, Drug Design, Protein Engineering, Proto-Oncogene Proteins p21(ras), Small Molecule Libraries
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